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| Home > Publications database > Chemoenzymatische Synthese optisch aktiver $\beta,\delta$-Dihydroxyester |
| Home > Publications database > Chemoenzymatische Synthese optisch aktiver $\beta,\delta$-Dihydroxyester |
| Dissertation / PhD Thesis/Book | PreJuSER-33330 |
2002
Forschungszentrum Jülich GmbH Zenralbibliothek, Verlag
Jülich
Please use a persistent id in citations: http://hdl.handle.net/2128/117
Report No.: Juel-3988
Abstract: A new access to optically active $\beta, \delta$-dihydroxy esters and $\delta$-hydroxy-$\beta$-keto esters is presented. These compunds are valuable intermediates for the synthesis of important natural products and pharmaceuticals, e. g. HMG-CoA reductase inhibitors of the mevinic acid type. The synthesis strategy is based on an unprecedented highly regio- and enantioselective biocatalytic reduction of achiral $\beta, \delta$-diketo esters. In a screening, two enantiocomplementary biocatalysts were found to be particularly suitable for this purpose. Thus, the $\beta, \delta$-diketo ester $\textit{tert}$-butyl 6-chloro-3,5-dioxohexanoate was reduced by NADP(H)-dependent alcohol dehydrogenase of $\textit{Lactobacillus brevis}$ to afford enantiomerically pure $\delta$-hydroxy-$\beta$-keto ester $\textit{tert}$-butyl (S)-6-chloro-5-hydroxy-3-oxohexanoate in a 72-84 % isolated yield (>99.5% ee). The enzyme is readily available in the form of a crude cell extract from a recombinant $\textit{E. coli}$ strain (recLBADH). A scale-up of the one-step substrate synthesis (140 g scale) and of the enzymatic reduction (70 g scale, substrate-coupled NADPH-regeneration) was established. The enantiomeric $\delta$-hydroxy-$\beta$-keto ester $\textit{tert}$-butyl (R)-6-chloro-5-hydroxy-3-oxohexanoate was obtained by reduction of $\textit{tert}$-butyl 6-chloro-3,5-dioxohexanoate with baker's yeast ($\textit{Saccharomyces cerevisiae}$). A detailed investigation of the reaction parameters of this whole-cell transformation led to the application of a biphasic system by which the enantiomeric excess could be raised from 48% ee to 94% ee (50% isolated yield). The $\beta$-keto group of both enantiomers thus obtained was reduced by $\textit{syn}$- and $\textit{anti}$-selective borohydride reductions. Combination of the reduction methods afforded all four stereoisomers of the crystalline $\beta, \delta$-dihydroxy ester $\textit{tert}$-butyl 6-chloro-3,5-dihydroxyhexanoate (>99% ee and $\textit{dr}$ > 200:1 each, 52-70% isolated yield). Alternatively, the $\textit{syn}$- (3R,5S)-isomer of this known building block was obtained in one step and with high stereoisomeric purity by reduction of $\textit{tert}$-butyl 6-chloro-3,5-dioxohexanoate with whole cells of $\textit{Lactobacillus kefir}$. An iodide and an epoxide suitable for C-C-bond formation at C-6 were derived from $\textit{tert}$-butyl $\textit{syn}$-(3R,5S)-6-chloro-3,5-dihydroxyhexanoate. recLBADH accepts a variety of $\beta, \delta$-diketo esters as was determined in a photometric assay. The $\beta, \delta$-diketo esters $\textit{tert}$-butyl 3,5-dioxohexanoate and $\textit{tert}$-butyl 3,5-dioxoheptanoate were reduced an a 1-10 mmol scale to afford the corresponding (R)-$\delta$-hydroxy-$beta$-keto esters with 99.4% ee and 98.1% ee, respectively (61-77 % isolated yield). The reduction ofthe branched $\beta, \delta$-diketo ester $\textit{tert}$-butyl $\textit{rac}$-4-methyl-3,5-dioxohexanoate proceeds via a dynamic kinetic resolution which resulted in a 66% isolated yield of the corresponding $\textit{syn}$-(4S,5R)-$\delta$-hydroxy-$beta$-keto ester (99.2% ee, dr = 35:1). To underline the applicability of the virtually enantiopure enzymatic products, they were used as starting materials for several new natural product syntheses. Furthermore, a convenient process for the large-scale separation of noncrystallising diastereomeric $\textit{syn}$- and $\textit{anti}$- 1,3-diols was developed. The crucial step of this new method is a diastereomer-differentiating hydrolysis of the respective acetonides.
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